Trafficking between clonally related peripheral T-helper cells and tissue-resident T-helper cells in chronic GVHD

•cGVHD is characterized by an expansion of Tph cells in the blood of patients and mice with cGVHD.•Clonally related Tph cells and Trh cells traffic between the blood and cGVHD target tissues. [Display omitted] Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome. CXCR5-PD-1hi per...

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Published in:Blood 2022-12, Vol.140 (25), p.2740-2753
Main Authors: Kong, Xiaohui, Wu, Xiwei, Wang, Bixin, Zeng, Deye, Cassady, Kaniel, Nasri, Ubaydah, Zheng, Moqian, Wu, Alyssa, Qin, Hanjun, Tsai, Weimin, Salhotra, Amandeep, Nakamura, Ryotaro, Martin, Paul J., Zeng, Defu
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - pathology
Bronchiolitis Obliterans Syndrome
CD4-Positive T-Lymphocytes
Chronic Disease
Graft vs Host Disease
Humans
Mice
Regular
T-Lymphocytes, Helper-Inducer
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Summary:•cGVHD is characterized by an expansion of Tph cells in the blood of patients and mice with cGVHD.•Clonally related Tph cells and Trh cells traffic between the blood and cGVHD target tissues. [Display omitted] Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome. CXCR5-PD-1hi peripheral T-helper (Tph) cells have an important pathogenic role in autoimmune diseases, but the role of Tph cells in cGVHD remains unknown. We show that in patients with cGVHD, expansion of Tph cells among blood CD4+ T cells was associated with cGVHD severity. These cells augmented memory B-cell differentiation and production of immunoglobulin G via interleukin 21 (IL-21). Tph cell expansion was also observed in a murine model of cGVHD. This Tph cell expansion in the blood is associated with the expansion of pathogenic tissue-resident T-helper (Trh) cells that form lymphoid aggregates surrounded by collagen in graft-versus-host disease (GVHD) target tissues. Adoptive transfer experiments showed that Trh cells from GVHD target tissues give rise to Tph cells in the blood, and conversely, Tph cells from the blood give rise to Trh cells in GVHD target tissues. Tph cells in the blood and Trh cells in GVHD target tissues had highly overlapping T-cell receptor α and β repertoires. Deficiency of IL-21R, B-cell lymphoma 6 (BCL6), or T-bet in donor T cells markedly reduced the proportions of Tph cells in the blood and Trh cells in GVHD target tissues and reduced T-B interaction in the lymphoid aggregates. These results indicate that clonally related pathogenic Tph cells and Trh cells traffic between the blood and cGVHD target tissues, and that IL-21R-BCL6 signaling and T-bet are required for the development and expansion of Tph and Trh cells in the pathogenesis of cGVHD. Kong and colleagues demonstrate a close relationship between pathologic features of chronic autoimmune disease and chronic graft-versus-host disease (cGVHD). The authors report that peripheral T helper cells (Tph), an important contributor to autoimmune diseases, are expanded in patients with cGVHD. Tph expansion correlates with increased pathogenic tissue-resident T helper (Trh) cells, which form lymphoid aggregates in target tissues. They further show that Tph and Trh cells traffic between the peripheral blood and target tissues in GVHD in an expansion dependent on IL-21R-BCL6 signaling.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2022016581